Agr2 in cancer and beyond: unraveling its role during protein synthesis, ER stress, and as a predictive biomarker

Abstract Protein folding is an essential component of protein biosynthesis, allowing for post-translational modifications that ensure proper protein structure and function to support cellular physiology. The presence of unfolded proteins triggers cellular mechanisms to either remove the unfolded proteins or reduce protein synthesis. However, the accumulation of improperly folded proteins may lead to diseases, including neurological disorders and cancers. Indeed, cancer cells have a dysregulated protein synthesis capacity that enables them to survive in higher proliferative and growth states. The anterior gradient 2 (Agr2) protein is often overexpressed in multiple cancers to support the need for increased protein synthesis resulting from uncontrolled cell proliferation. Agr2 acts like a protein disulfide isomerase (PDI), catalyzing the formation of disulfide bonds in native proteins. Its expression in cancers has been associated with increased cell proliferation, metastasis, and invasion. Conversely, the lack of Agr2 has been associated with ER stress (ERS) and the activation of the unfolded protein response (UPR) pathway to restore cellular protein homeostasis. Furthermore, Agr2 can be secreted into the extracellular environment and has been detected in human urine and serum, highlighting its potential use as a cancer biomarker. This review discusses Agr2 and its role in protein synthesis and ERS. We examine recent developments regarding its detection and use as a biomarker and delve into emerging therapeutic strategies focused on targeting Agr2.